PSEN1 gene

The PSEN1 gene (PSEN1 stands for: Presenilin 1) is a protein-coding gene located on chromosome 14q24.2. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene; the complete sequence of some of these variants is not yet known. Gene ontology (GO) annotations of this gene include peptidase activity and β-catenin binding. An important paralog of this gene is PSEN2.

The protein encoded by the PSEN1 gene is a catalytic subunit of the gamma-secretase complex, an endoprotease complex. This complex can be described as an integral membrane protein and consists of at least four proteins: presenilin, nicastrin, APH-1 and PEN-2 (Yang G et al. 2019; Zhou R et al. 2019). It catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid beta precursor protein) (Wolfe MS et al. 1999; Yang G et al. 2019). The gamma-secretase enzyme complex plays a role in the Notch and Wnt signaling pathways and in the regulation of downstream processes, e.g. in the regulation of cytosolic CTNNB1 levels (Murayama M et al. 1998).

The PSEN1 protein stimulates cell-cell adhesion through its interaction with CDH1 (E-cadherin). This stabilizes the complexes between E-cadherin and its interaction partners β-catenin (CTNNB1 ), CTNND1 and γ-catenin (JUP ) (Marambaud P et al. 2002). Thus, it cleaves CDH1 under apoptotic conditions (Marambaud P et al. 2002). This promotes the dissociation of the complexes between CDH1 (E-cadherin), as well as JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1 and thereby negatively regulates Wnt signaling (Murayama M et al. 1998). The holoprotein acts as a calcium channel regulator that enables the passive transport of calcium from the endoplasmic reticulum into the cytosol and is thus involved in calcium homeostasis (Chen WT et al. 2015). The protein is also involved in the regulation of neurite outgrowth. It regulates presynaptic facilitation, spike transmission and replenishment of synaptic vesicles in a process that depends on gamma-secretase activity.

Diseases associated with PSEN1 include dilated cardiomyopathy type 1U and Alzheimer's disease. Patients with a hereditary form of Alzheimer's disease (AD) have mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein(APP). These disease-associated mutations lead to increased production of the longer form of amyloid beta(the main component of amyloid deposits in the brains of AD patients). Presenilins are thought to regulate APP processing through their effect on gamma-secretase, an enzyme that cleaves APP. In addition, presenilins are thought to be involved in Notch receptor cleavage by either directly regulating the activity of gamma-secretase or by acting as proteases themselves.

1. Chen WT et al. (2015) G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation. Mol Neurobiol 52:1835-1849.
2. Marambaud P et al. (2002) A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 21:1948-1956.
3. Murayama M et al. (1998) Direct association of presenilin-1 with beta-catenin. FEBS Lett 14;433 (1-2):73-77.
4. Wolfe MS et al. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513-517.
5. Yang G et al. (2019) Structural basis of Notch recognition by human γ-secretase. Nature 565:192-197.
6. Zhou R et al. (2019) Recognition of the amyloid precursor protein by human γ-secretase. Science 363:eaaw0930.